Alteration of systemic and uterine endometrial immune populations in patients with endometriosis

Abstract

Problem: Endometriosis is defined as growth of endometrial tissue in ectopic locations; it is associated with infertility and chronic pain and affects ~12% of reproductiveaged women. Although inflammation is known to play a key role in endometriosis, knowledge related to immune phenotypes associated with this disease is lacking. This study aimed to characterize immune profiles in patients with endometriosis, to assess inflammatory mediators, to and determine if surgical and/or hormonal therapies restore immune homeostasis. Methods of study: Samples from nine controls and 20 histologically confirmed endometriosis patients were collected upon surgery and ~1-3 weeks post-surgical intervention. Subjects were either not utilizing hormonal suppression or were currently on monophasic hormonal therapy. Tolerant regulatory T cells (Tregs = natural [nTregs] +inducible [iTregs]) and inflammatory T helper 17 (Th17) cells were identified in peripheral blood via flow cytometry and within the eutopic/ectopic endometrial tissues via immunohistochemistry and real-time-qPCR. Cytokines were assessed via 10-plex-ELISA. Results: Patients with endometriosis not utilizing hormonal therapy exhibited lower iTregs (tolerant), greater Th17 (inflammatory), and a reduction in Treg/Th17 ratio (P < .05), indicative of systemic inflammation. Treg and Th17 localizations were enhanced within the ectopic endometrial implant, which promotes lesion development. Hormonal therapy decreased systemic and local inflammation (eutopic/ectopic endometrium) via decreased iTregs and Th17 cells in patients with endometriosis (P < .05). Thus, imbalance within immune populations correlated with increased inflammation in patients with endometriosis, which was mitigated by hormonal therapy. Conclusions: Patients with endometriosis exhibited systemic and localized inflammation within ectopic and endometrial tissues. Hormonal therapy dampened inflammation caused by disease.

Altered eutopic endometrial T-regulatory and T-helper 17 lymphocyte ratio in women with unexplained subfertility

“…Le et al have recently reported an increased accumulation of Th17 cells and reduction in Treg cells in the peripheral circulation and ectopic endometrial tissue in patients with endometriosis, that seemed to be mitigated by hormone therapy but not by surgical removal of ectopic lesions. 40 All these previous studies support our findings that the low Treg and concurrent high Th17 cell phenotype is potentially responsible for the unsuccessful conception status in the subfertile patients with concurrent endometriosis, even after laparoscopic removal of ectopic lesions.…”

“…Interleukin-17 (IL-17) is significantly higher in the peritoneal fluid of patients with minimal/mild stage endometriosis as compared to those with moderate/severe stage of disease. 41,42 Other studies have also shown abnormal serum 40 and peritoneal fluid 42 T-cell related cytokine levels in patients with endometriosis. IL-17 acts through the induction and expression of other pro-inflammatory cytokines and chemokines, 37 which mediate immune cell infiltration, angiogenesis and maintenance of endometriotic lesions.…”

Effects of endometriosis on immunity and mucosal microbial community dynamics in female olive baboons

“…Inflammatory Th17 cells are derived from the CD4 lineage of T cells that secrete interleukin-17 (IL17s), IL21, IL22 and express the RAR-related orphan receptor gamma transcription factor (RORγt), to activate cytotoxic CD8 + T cells. Plasma and peritoneal fluid levels of IL-17 are elevated in endometriosis patients and we, along with others, have reported that Tregs and Th17 immune cell populations contribute to the systemic and tissue specific inflammatory profile of patients with endometriosis 13 , 14 . Briefly we found low levels of peripheral Tregs, greater Th17 cell populations and an increase in the Th17/Treg ratio, indicative of systemic inflammation 14 .…”

“…Plasma and peritoneal fluid levels of IL-17 are elevated in endometriosis patients and we, along with others, have reported that Tregs and Th17 immune cell populations contribute to the systemic and tissue specific inflammatory profile of patients with endometriosis 13 , 14 . Briefly we found low levels of peripheral Tregs, greater Th17 cell populations and an increase in the Th17/Treg ratio, indicative of systemic inflammation 14 . We also reported that Tregs and Th17 localizations were enhanced within the ectopic endometrial implant, which promotes lesion development via induce angiogenesis 14 .…”

“…Briefly we found low levels of peripheral Tregs, greater Th17 cell populations and an increase in the Th17/Treg ratio, indicative of systemic inflammation 14 . We also reported that Tregs and Th17 localizations were enhanced within the ectopic endometrial implant, which promotes lesion development via induce angiogenesis 14 . Earlier studies using the baboon model demonstrated that the induction of endometriosis resulted in reduction of Tregs in the peripheral circulation and endometrium 12 .…”